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(Circulation Research. 2000;87:289.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Endotoxemia in Transgenic Mice Overexpressing Human Glutathione Peroxidases

Oleg Mirochnitchenko, Olga Prokopenko, Urmila Palnitkar, Ilya Kister, William S. Powell, Masayori Inouye

From the Department of Biochemistry (O.M., O.P., U.P., I.K., M.I.), Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, and Meakins-Christie Laboratories (W.S.P.), Department of Medicine, McGill University, Montreal, Quebec, Canada.

Correspondence to Oleg Mirochnitchenko, Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854. E-mail mirochol{at}rwja.umdnj.edu

Abstract—In response to endotoxemia induced by administration of lipopolysaccharide, a complex series of reactions occurs in mammalian tissues. During this inflammation response, cells produce different mediators, such as reactive oxygen species, a number of arachidonic acid metabolites, and cytokines. The reactive oxygen species thus generated have been suggested to produce tissue injury as a result of macromolecular damage or by interfering with regulatory processes. They may also act as important signaling molecules to induce redox-sensitive genes. We report here that transgenic mice overexpressing 2 major forms of human glutathione peroxidases (GPs), intra- and extracellular GP, are able to modulate host response during endotoxemic conditions. We show that these animals have a decreased hypotension and increased survival rate after administration of a high dosage of lipopolysaccharide. Overexpression of GPs alters vascular permeability and production of cytokines (interleukin-1ß and tumor necrosis factor-) and NO, affects arachidonic acid metabolism, and inhibits leukocyte migration. These results suggest an important role for peroxides in pathogenesis during endotoxemia, and GPs, by regulating their level, may prove to be good candidates for antioxidant therapy to protect against such injury.

Key Words: endotoxemia • oxidative stress • glutathione peroxidase

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